Vascular diseases such as coronary heart disease, stroke, restenosis, and peripheral vascular disease, remain the leading cause of death and disability throughout the world. About 1.5 million people die each year in the United States alone from myocardial infarction resulting from congestive heart failure. While diet and life style can accelerate the onset of vascular diseases, genetic predisposition leading to dyslipidemia is a significant factor in vascular-related disabilities and deaths. “Dyslipidemia” means abnormal levels of lipoproteins in blood plasma.
Several risk factors have been associated with increased risk of vascular disease. Among these are the dyslipidemias of high levels of low-density lipoprotein (LDL) and low levels of high-density lipoproteins (HDL). The ratio of HDL-cholesterol to LDL-cholesterol is often used to assess the risk of vascular disease. A high ratio of HDL/LDL cholesterol is desirable. Compounds that increase this ratio by either lowering LDL or increasing HDL, or both, therefore are beneficial.
Studies also have shown that elevated levels of a modified form of LDL designated as lipoprotein(a), “Lp(a),” are detrimental. Elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, stroke, cerebral infarction, and restenosis following balloon angioplasty. In fact, Lp(a) appears to be an excellent predictor of stroke potential. Accordingly, high concentrations of cholesterol in the form of Lp(a) are one of the major factors leading to death from heart disease. Compounds that lower Lp(a) are therefore beneficial.
U.S. Pat. No. 5,648,387 discloses 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid and its effectiveness in lowering plasma concentrations of Lp(a), and in increasing HDL. The formation of pharmaceutically acceptable salts from the carboxylic acid is also described, for example, by reaction with bases including sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, triethylamine, pyridine, and ammonia. Owing to the low melting character of the carboxylic acid and the lack of crystallinity and hygroscopic nature of the contemplated salts thereof, drying and crystallization of large quantities such as mass production lots remains inconsistent. Thus, there exists a need for a salt of the carboxyalkyl ether which is effective in raising HDL, lowering plasma Lp(a), which is crystalline so it can be manufactured and processed on a commercial scale, and which is amenable to pharmaceutical formulation for the treatment of vascular disease. This invention provides a salt form that satisfies these needs.